The present invention generally relates to the diagnosis and treatment of neurological and neuropsychiatric diseases. More specifically, this invention relates to the diagnosis and treatment of neurological and neuropsychiatric diseases using electromagnetic and frequency analysis techniques.
The major theory of motor and cognitive functions hypothesizes that motor and cognitive functions arise from coordinate electrical activity at the cortical level of the brain. Coordinate electrical activity refers to controlled electrical discharges within the brain at both cellular and macrocellular levels. Controlled electrical discharges facilitate communication within and among different regions of the cortex, and thus coordinate electrical activity through controlled electrical discharges at the cortical level of the brain gives rise to motor and cognitive abilities.
At the cellular level, neurons within the brain interact and communicate through electrical signals that are sent between neurons. Neurons send electrical signals via an electrochemical process, wherein an exchange of ions occurs through a neuron""s membrane, thereby causing an electrical discharge. When a neuron is in its rest state, the neuron accumulates and maintains a negative charge within its membrane, thereby polarizing a negative potential (typically xe2x88x9270 mV) between the inside and outside of the neuron. The neuron discharges when a stimulus event increases the negative membrane potential beyond a certain threshold value (typically xe2x88x9255 mV), thereby triggering an exchange of ions across the neuron""s membrane and depolarizing the neuron. The depolarization and exchange of ions causes a positive discharge, also known as a xe2x80x9cspikexe2x80x9d or xe2x80x9cimpulse,xe2x80x9d that peaks at a net positive potential (typically +30 mV). This positive discharge is sent from the neuron through its axon(s) to the dendrites of recipient neurons, which receive the electrical signal. After the positive discharge, the transmitting neuron returns to its rest state, thereby completing the discharge cycle.
The stimulus event that causes the discharge of a transmitter neuron may occur because of the effect of an inhibitor neuron on the transmitter neuron. An inhibitor neuron acts to prevent the discharge of other neurons, and thus provides a negative feedback mechanism that prevents the discharge of these neurons by maintaining a negative membrane potential. When the inhibitor neuron is itself inhibited, however, then its negative feedback becomes positive, thereby raising the membrane potential to the threshold level and causing those neurons it had been inhibiting to discharge. Thus, inhibitor neurons control the electrical discharge of other neurons.
Stimulus events that affect the discharge of a transmitter neuron may also occur independently of an inhibitor neuron. In particular, the sensory input received by a transmitter neuron may control the discharge of the transmitter neuron. Thus, the general chemical and physiological components around the neuron themselves affect the discharge of a neuron irrespective of inhibitor neurons. As a result, neurotransmitters and other chemical and physiological components may influence the discharge of a neuron.
At the macrocellular level, different regions of the brain are responsible for different cognitive and motor functions. Different layers of the cortex, which is the outer layer of the brain, control different cognitive and motor skills including speech, hearing, sight, touch, smell and thought. The cortex itself has six main cellular levels of neurons (levels I-VI) wherein intracellular communication takes place via electrical impulses. Thus, normal cognitive and motor functions are the product of coordinate electrical activity that occurs at the cortical level.
Also at the macrocellular level, the thalamus resides within the center of the brain and acts as a xe2x80x9ccommunications hubxe2x80x9d between different regions of the brain, including the cortex. The normal electrical activity of the thalamus is also coherent, in the sense that the thalamus fires electrical impulses at specific intervals and in a controlled fashion. A plurality of neurons exist between the thalamus and the cortex, thereby creating corticothalamic pathways that facilitate communication and interaction between the thalamus and the cortex.
The thalamus itself is divided into regions that include the sensory thalamus and the reticular nucleus. The sensory thalamus is stimulated by signals from other sensory inputs from the body and communicates those inputs to the cortex. The reticular nucleus surrounds the sensory thalamus and acts to suppress the sensory thalamus from transmitting signals at certain times, such as sleep, when the cortex is to be desensitized from communication with the rest of the body. Thus, the reticular nucleus suppresses the electrical activity and discharge of the sensory thalamus.
The thalamus and the cortex are connected through specific and nonspecific corticothalamic pathways. Specific pathways refer to pathways between the thalamus and particular sensory or motor input regions of the cortex, typically connecting at layer IV of the cortex. Nonspecific pathways refer to pathways between the thalamus and non-sensory and non-motor input regions of the cortex, typically connecting at layers I, IV and V of the cortex. Afferent corticothalamic pathways communicate signals from the thalamus to the cortex, whereas efferent corticothalamic pathways communicate signals from the cortex to the thalamus, thereby closing the communication loop between the cortex and the thalamus.
Coordinate electrical activity is characterized by normal neuronal oscillation (i.e., normal frequencies of electrical oscillation by neurons and neuronic regions), wherein neurons and neuronic regions of the brain discharge electrical impulses at particular frequencies, thereby causing electrical oscillation. At the cellular level, inhibitors and neuronal inputs properly control the chemical release of neurons and thereby facilitate normal electrical discharges by the neurons. At the macrocellular level, the interaction and communication between properly discharging neurons causes normal, coordinate electrical activity characterized by electrical oscillation at different frequencies between and among particular regions of the brain.
Neuronal oscillation generally occurs in a plurality of distinct frequency bands. These frequency bands include the theta (xcex8) band, which includes low frequency oscillations in the 4-8 Hz range, and are most commonly associated with the four-phase sleep cycle of human beings. These frequency bands also include the gamma (xcex3) band, which includes high frequency oscillations in the 20-50 Hz range, and which are associated with sensorimotor and cognitive functions. Individuals experience specific types and amounts of theta- and gamma-band activity based on factors including their mental activity level and physical state. For instance, a person who is asleep will typically experience the four-phase theta-band oscillation cycle associated with sleep, whereas a person who is awake and active will experience gamma-band oscillation at the cortical level to perform cognitive and motor functions.
Neuropsychiatric diseases occur when the coordinate, controlled electrical activity at the cortical level of the brain becomes disrupted, thereby leading to uncoordinated electrical activity and abnormal neuronal oscillation. Neuropsychiatric diseases include but are not limited to neurogenic pain, obsessive-compulsive disorder, depression, panic disorder, Parkinson""s disease, schizophrenia, rigidity, dystonia, tinnitus and epilepsy. In particular, these and other neuropsychiatric diseases are characterized by thalamocortical dysrhythmia, wherein the electrical oscillation levels and frequencies for different portions of the cortex and thalamus deviate from the oscillation levels and frequencies that exist for persons who do not suffer from neuropsychiatric diseases. Such deviations occur at both the cellular and macrocellular level, and these deviations interfere with the communication among and between different regions of the brain. When this interference occurs in specific regions of the cortex, the interference impairs the motor and cognitive skills that are controlled by those regions of the cortex. This interference manifests itself in the positive symptoms of neuropsychiatric disease that are caused by the interference that occurs in different cortical regions.
It has been generally known that normal neuronal oscillation is characterized by neuronal activity at certain frequencies for certain neurological diseases. In addition, numerous invasive and non-invasive methods of measuring the neuronal oscillation at the cortical level are known, including electroencephalography (EEG), magnetoencephalography (MEG). Thus, certain conventional methods are able to determine the presence or absence of neuropsychological diseases based on measurements of neuronal oscillation at the cortical level.
None of these known methods describes the precise nature of neuronal oscillations, including their characteristics and degree of deviation from normal neuronal oscillation patterns. In fact, none of the known methods disclose what characterizes a suitable baseline of normal neuronal oscillation, what is considered a deviation from a suitable baseline of normal neuronal oscillation, and most important, what mechanism causes deviations from the baseline of normal neuronal oscillation that causes neuropsychiatric disease. Thus, although known methods describe the general and unremarkable principles of neuronal oscillation and use of neuronal oscillation measurements as a basis to diagnose and treat neuropsychiatric diseases, none of these methods describe or disclose precisely how to diagnose neuropsychiatric diseases that are caused by thalamocortical dysrhythmia. Without the ability to describe the nature of normal neuronal oscillation and the significance of deviations from normal neuronal oscillation, the ability to diagnose a patient who may suffer from neuropsychiatric diseases caused by thalamocortical dysrhythmia through measurement of the patient""s neuronal oscillation is at the least incomplete, and at the best ineffective.
These and other deficiencies in the prior art are addressed by the present invention, which is a method and system for diagnosing and treating thalamocortical dysrhythmia. In particular, the present invention describes the mechanisms that cause thalamocortical dysrhythmia, the characteristics of normal neuronal oscillation and the deviations from normal neuronal oscillation that characterize thalamocortical dysrhythmia. The present invention also describes a method for diagnosis and treatment of thalamocortical dysrhythmia based on these mechanisms, characteristics, and deviations. Thus, the present invention describes a method to measure, record and process electrical activity in the brain, and more specifically the cortex, to diagnose thalamocortical dysrhythmia and prescribe a treatment.
At the cellular level, neuronal cells have individual properties and characteristics within the general neuronal system. Thus, specific neuronal cells are constructed to operate at specific frequencies during different times. When operating nominally, thalamic cells oscillate in the gamma range, typically at 40 Hz, while in the xe2x80x9cawakexe2x80x9d or active state, and oscillate in the theta range, typically at 4 Hz, while in the xe2x80x9casleepxe2x80x9d or inactive state.
Thalamocortical dysrhythmia occurs within the thalamus when thalamic neurons that should be in the active state become imbalanced or hyperpolarized and enter the inactive state while an individual is awake. When such an imbalance takes place, the thalamic cells enter an abnormal xe2x80x9casleepxe2x80x9d state wherein they fail to communicate information properly to the cortex through the corticothalamic pathways. This causes the cortex itself to become imbalanced, thereby disrupting coherent electrical activity at the cortical level and causing thalamocortical dysrhythmia.
The change of thalamic neurons from the active to the inactive state may have multiple causes, primarily including overstimulation or under stimulation by inputs to thalamic neurons, and also including excessive inhibition by inhibitor neurons. Thalamic neurons become hyperpolarized, wherein the membrane potential for the neuron""s rest state and/or threshold potential changes, as well as changing the actual discharge characteristics of the neuron itself. As a result, the thalamic neurons overcharge and decrease the periodicity of their discharge, which causes abnormally high theta-band oscillation as thalamic neurons send out electrical impulses too late (at a lower frequency) and at a higher amplitude. Thus, within the thalamus, the net result is a shift in neuronal oscillation to lower frequencies and an increased amplitude.
Temporal coherence of these theta-band oscillations occurs at the thalamic level through the corticothalamic pathway loops between the thalamus and the cortex. The theta-band oscillations propagate to the cortex through afferent corticothalamic pathways, and then return to the thalamus through efferent corticothalamic pathways, thereby feeding the theta-band oscillations back to the thalamus. This causes large scale temporal coherence at the thalamic level, as thalamic neurons become synchronized with the theta-band oscillation. This temporal coherence is further driven at the thalamic level through thalamic pathways between neighboring thalamic neurons, as well as common inputs between and among neighboring thalamic cells that are the source of the theta-band oscillations. Thus, the common effect of the corticothalamic pathways, thalamic-level pathways between neighboring thalamic cells, and common thalamic inputs is large scale, theta-band oscillation in the thalamic level, typically at 4 Hz.
Temporal coherence of theta-band oscillations also occurs at the cortical level through the afferent corticothalamic pathways. The theta-band oscillations travel through the afferent corticothalamic pathways to corresponding cortical level neurons, which are linked to the thalamic level neurons as part of a single corticothalamic module. Thus, cortical level neurons become synchronized with their corresponding thalamic neurons in theta-band oscillation, thereby providing temporal coherence between the thalamic and cortical neurons within a single corticothalamic module.
The prevalence and amplitude of gamma-band oscillations at the cortical level also increase from the thalamic interaction with cortical inhibitory neurons. Specifically, afferent specific corticothalamic pathways connect thalamic neurons to cortical inhibitory neurons. The decreased frequency of the theta-band oscillation from thalamic neurons reduces the lateral inhibition of the cortical inhibitory neurons, thereby deinhibiting otherwise normal cortical neurons. This loss of inhibition allows these cortical neurons to increase their high frequency oscillations, thereby causing abnormally high gamma-band oscillation within the cortex. This gamma-band oscillation is temporally coherent with the theta-band oscillation, as the temporally coherent theta-band oscillation is the cause of the gamma-band oscillation. In particular, unlike a normal individual, there is a simultaneous presentation of both theta-band and gamma-band oscillation within the cortex. Thus, an abnormal correlation exists between the increased theta-band and gamma-band oscillation. In other words, whereas normally there is little correlation between theta- and gamma-band oscillation, in an abnormal condition such correlation arises from the simultaneous presence of theta- and gamma-band oscillation, and such abnormal correlation is characteristic of thalamocortical dysrhythmia.
The abnormal temporal coherence and correlation between theta- and gamma-band frequencies, as well as within the theta-band itself, is significant because normal individuals that do not suffer from thalamocortical dysrhythmia may experience a low amount of theta-band oscillation when they are awake and active. For instance, some theta-band neuronal oscillations have been observed, particularly in the rostral pole area, for individuals that are awake and who do not have thalamocortical dysrhythmia. Thus, the mere presence of theta-band neuronal oscillations at the cortical level may be insufficient to diagnose an individual as having thalamocortical dysrhythmia. However, the theta-band neuronal oscillations that sometimes occur in individuals without thalamocortical dysrhythmia are not temporally coherent or correlated as are the theta-band neuronal oscillations for individuals with thalamocortical dysrhythmia. Therefore, the temporal coherence and abnormal correlation of theta-band neuronal oscillations act to distinguish theta-band neuronal oscillations of individuals with thalamocortical dysrhythmia, and theta-band neuronal oscillations of individuals without thalamocortical dysrhythmia. The present invention uses this temporal coherence and correlation to separate theta-band oscillations caused by thalamocortical dysrhythmia from those that are not caused by thalamocortical dysrhythmia.
At the macrocellular level, these oscillatory deviations interfere with the normal coordinate electrical activity necessary for brain functionality and cause neuropsychiatric disease. The primary characteristics of neuropsychiatric disease therefore include an overall increase in the amplitude of theta- and gamma-band oscillations, an increased correlation and temporal coherence between theta- and gamma-band oscillations, and an overall shift toward theta-band frequencies. In particular, at the cortical level, the increased levels of gamma-band oscillations within and among particular cortical regions interfere with the motor and/or cognitive functions controlled by those regions. For example, oscillatory deviations in the auditory cortex or medial geniculate nucleus may cause tinnitus (ringing of the ears), whereas oscillatory deviations in the cingulate cortex may cause depression.
The ability to measure neuronal rhythmicity provides the ability to diagnose individuals who suffer from neuropsychiatric diseases caused by thalamocortical dysrhythmia. In particular, the ability to measure the neuronal rhythmicity in particular cortical regions and correlate such rhythmicity with the rhythmicity associated with neuropsychiatric diseases allows the diagnosis of neuropsychiatric disease. By analyzing the particular cortical regions, their neuronal oscillation frequencies, their neuronal oscillation amplitudes, and their neuronal oscillation correlations, the present invention may be used to diagnose an individual as suffering from thalamocortical dysrhythmia.
In accordance with the present invention, the electrical activity of a patient""s brain is measured at the cortical level. In particular, the present invention may use techniques that include magnetoencephalography (MEG) and electroencephalography (EEG) to measure and record electrical activity for particular cortical regions. A Fourier transform of the electrical data then determines the neuronal rhythmicity, i.e., the electrical oscillation frequencies, of regions of the cortex. The present invention is thereby able to determine the neuronal rhythmicity for both the cortex as a whole, as well as for particular regions of the cortex.
Once the neuronal rhythmicity has been determined, the present invention processes the neuronal rhythmicity data to determine whether the data is characteristic of thalamocortical dysrhythmia. In particular, the present invention determines whether the data demonstrates the presence or indicia of abnormal neuronal rhythmicity that is associated with thalamocortical dysrhythmia and different neuropsychiatric diseases. The present invention processes the neuronal rhythmicity data to determine whether thalamocortical dysrhythmia exists, and then diagnoses the neuropsychiatric disease(s) of the patient based on the presence of thalamocortical dysrhythmia.
The present invention may determine the presence of indicia of abnormal neuronal rhythmicity in a plurality of ways. First, thalamocortical dysrhythmia is characterized by higher overall amplitude of neuronal activity as well as a higher ratio of theta-band oscillations to gamma-band oscillations. Any comparative increase in the amplitude of neuronal activity or frequency shift toward prevalence of theta-band oscillations indicates the presence of thalamocortical dysrhythmia. Such a comparative increase may be relative to the patient himself based on prior data regarding neuronal activity, or may be relative to other standards of normal neuronal activity independent of the individual patient. Thus, the present invention diagnoses that an individual is suffering from thalamocortical dysrhythmia by determining that the amplitude or theta-to-gamma ratio of the individual""s neuronal oscillations have notably deviated from a reference baseline of amplitude or theta-to-gamma ratio data.
Second, thalamocortical dysrhythmia is characterized by abnormally high correlation between neuronal oscillation frequencies, such as low frequency theta-band and high frequency gamma-band neuronal oscillations. The present invention is able to correlate the different frequencies of neuronal activity to determine the correlation between theta- and gamma-band neuronal oscillations. Any comparative increase in the correlation between theta- and gamma-band neuronal oscillations indicates the presence of thalamocortical dysrhythmia. Such a comparative increase may be relative to the patient himself based on prior data regarding neuronal activity, or may be relative to other standards of normal neuronal activity independent of the individual patient. Thus, the present invention diagnoses that an individual is suffering from thalamocortical dysrhythmia by determining that the correlation of theta-band to gamma-band neuronal oscillations for the individual has notably deviated from a reference baseline of theta-band to gamma-band oscillation correlation.
The present invention can also determine whether thalamocortical dysrhythmia exists for different, specific cortical regions. In particular, the present invention can identify the cortical area(s) where thalamocortical dysrhythmia is present and the nature of the thalamocortical dysrhythmia, including deviant amplitudes of neuronal oscillation, deviant theta-band to gamma-band oscillation ratios, and deviant theta-band to gamma-band correlation. These identifications are compared with the known cortex regions and the nature of the thalamocortical dysrhythmia, as well as with the patient""s symptoms to determine the neuropsychiatric disease(s) that afflict the patient. A doctor or other medical professional is then able to prescribe a course of treatment based both on the general neuropsychiatric disease(s) affecting the patient, as well as the precise area and nature of the thalamocortical dysrhythmia that is the cause of the disease(s). Appropriate methods of treatment may include, but are not limited to, surgical treatments such as cortical ablation, electrical treatments such as implanting electrodes for neural stimulation, and pharmacological treatments.